Aberrant activation of the Wnt/β-catenin signaling pathway is a critical event in advanced prostate cancer, but the genetic alterations which activate the Wnt signaling pathway in many other cancers are rarely observed in prostate cancer. Other molecular mechanisms that regulate the Wnt signaling pathway in prostate cancer remain to be identified. Here it is demonstrated that KIF3a, a subunit of kinesin-II motor protein, functions as an agonist of the Wnt signaling pathway in prostate cancer. KIF3a is up-regulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3a correlate with a higher Gleason score, TNM grade, and metastatic status of prostate cancer. Moreover, exogenous expression of KIF3a promoted cell growth in the benign prostate cells, whereas silencing KIF3a in cancer cells decreased cell proliferation, anchorage-independent cell growth, and cell migration/invasion. Mechanistically, KIF3a increases CK1-dependent DVL2 phosphorylation and β-catenin activation in prostate cancer cells, leading to transactivation of the Wnt signaling target genes such as Cyclin D1, HEF1, and MMP9. These findings support the notion that up-regulation of KIF3a is causal of aberrant activation of Wnt signaling in advanced prostate cancer through the KIF3a-DVL2-β-catenin axis. Implications Inactivation of KIF3a may improve survival of patients with advanced prostate cancer in which Wnt signaling is activated.

Aberrant activation of the Wnt signaling pathway is a key event in advanced prostate cancer. However, the mutations in APC complex that activate Wnt signaling in many other cancers are rare in prostate cancer. Other molecular mechanisms that regulate the Wnt signaling pathway in prostate cancer remain to be elucidated. Here we show that KIF3A, a subunit of kinesin-II motor protein, functions as an agonist of the Wnt signaling pathway in prostate cancer. KIF3A is up-regulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3A correlate with higher Gleason score, TNM grade, and metastatic status of prostate cancer. Moreover, overexpression of KIF3A stimulates the benign p69 prostate cell growth, whereas depletion of KIF3A by shRNA suppresses LNCaP cell proliferation, anchorage-independent growth, and cell migration/invasion. Mechanistically, we demonstrate that KIF3A activates DVL2 and induces transcriptional activation of Cyclin D1, HEF1, and MMP9 in prostate cancer cell lines that are required for cancer cell proliferation, migration, and invasion. Taking together, these findings indicate that KIF3A is a potent agonist of Wnt signaling in prostate cancer and suggest that up-regulation of KIF3A is causal of aberrant activation of Wnt signaling in advanced prostate cancer. Inactivation of KIF3A may improve survival of patients with advanced prostate cancer in which Wnt signaling is activated. Citation Format: Zun Liu, Ryan E. Rebowe, Zemin Wang, Zehua Wang, John S. DePaolo, Jianhui Guo, Yingchun Li, Chiping Qian, Wanguo Liu. KIF3A promotes prostate cancer cell proliferation, migration, and invasion via activation of Dvl2 and the Wnt signaling pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4937. doi:10.1158/1538-7445.AM2013-4937

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